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Mechanisms and management of refractory coeliac disease

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Key Points

  • The most common cause of persistent villous atrophy is inadvertent gluten exposure, but refractory coeliac disease can occur

  • Autoimmune enteropathy, common variable immune deficiency and olmesartan-related enteropathy should be excluded in instances of persistent villous atrophy

  • Type II refractory coeliac disease is now considered a low-grade, no-mass lymphoma

  • Patients with enteropathy-associated T-cell lymphoma and refractory coeliac disease should be treated in dedicated coeliac and small bowel disease centres


A small subset of patients with coeliac disease become refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. The most common cause of this condition is inadvertent gluten exposure, but concomitant diseases leading to villous atrophy should also be considered and excluded. After exclusion of these conditions, patients are referred to as having refractory coeliac disease, of which two categories are recognized based on the absence (type I) or presence (type II) of a clonal expansion of premalignant intraepithelial lymphocyte population with a high potential for transformation into an overt enteropathy-associated T-cell lymphoma. Type I disease usually has a benign course that can be controlled by mild immunosuppressive treatment, but type II can be more severe with cladribine with or without autologous stem cell transplantation effective as treatment. Patients who fail to respond to cladribine therapy, however, still have a high risk of malignant transformation. Insights into the immunophenotype of these cells and the recognition that type II disease is a low-grade, no-mass lymphoma opens avenues for new treatment strategies, including chemotherapeutic and immunomodulating strategies. This Review will provide an overview of refractory coeliac disease, discussing mechanisms, diagnosis and management.

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Figure 1: Characteristics of coeliac disease and RCD.
Figure 2: Diagnostic approach for patients with suspected refractory coeliac disease.

Change history

  • 16 September 2015

    In the version of this article originally published online, HLA-DQ2 and fludarabine were misspelled in Figure 1. These errors have been corrected for the PDF, HTML and print versions of the article.


  1. 1

    Castillo, N. E., Theethira, T. G. & Leffler, D. A. The present and the future in the diagnosis and management of celiac disease. Gastroenterol. Rep. (Oxf.) 3, 3–11 (2014).

    Article  Google Scholar 

  2. 2

    Al-Toma, A., Verbeek, W. H. & Mulder, C. J. Update on the management of refractory coeliac disease. J. Gastrointest. Liver Dis. 16, 57–63 (2007).

    Google Scholar 

  3. 3

    Wahab, P. J., Meijer, J. W. & Mulder, C. J. Histologic follow-up of people with celiac disease on a gluten-free diet: slow and incomplete recovery. Am. J. Clin. Pathol. 118, 459–463 (2002).

    Article  Google Scholar 

  4. 4

    Lanzini, A. et al. Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet. Aliment. Pharmacol. Ther. 29, 1299–1308 (2009).

    CAS  Article  Google Scholar 

  5. 5

    Kaukinen, K. et al. Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease. Aliment. Pharmacol. Ther. 25, 1237–1245 (2007).

    CAS  Article  Google Scholar 

  6. 6

    United European Gastroenterology. When is a coeliac a coeliac? Report of a working group of the United European Gastroenterology Week in Amsterdam. Eur. J. Gastroenterol. Hepatol. 13, 1123–1128 (2001).

  7. 7

    Al-Toma, A., Verbeek, W. H., Hadithi, M, von Blomberg, B. M. & Mulder, C. J. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut 56, 1373–1378 (2007).

    CAS  Article  Google Scholar 

  8. 8

    Rubio-Tapia, A. et al. Clinical staging and survival in refractory celiac disease: a single center experience. Gastroenterology 136, 99–107 (2009).

    Article  Google Scholar 

  9. 9

    Malamut, G. et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology 136, 81–90 (2009).

    Article  Google Scholar 

  10. 10

    West, J. Celiac disease and its complications: a time traveller's perspective. Gastroenterology 136, 32–34 (2009).

    Article  Google Scholar 

  11. 11

    Roshan, B. et al. The incidence and clinical spectrum of refractory celiac disease in a North American referral center. Am. J. Gastroenterol. 106, 923–928 (2011).

    Article  Google Scholar 

  12. 12

    Wolters, V. M. & Wijmenga, C. Genetic background of celiac disease and its clinical implications. Am. J. Gastroenterol. 103, 190–195 (2008).

    Article  Google Scholar 

  13. 13

    Al-Toma, A. et al. Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin. Gastroenterol. Hepatol. 4, 315–319 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Di, S. A., Biagi, F., Gobbi, P. G. & Corazza, G. R. How I treat enteropathy-associated T-cell lymphoma. Blood 119, 2458–2468 (2012).

    Article  Google Scholar 

  15. 15

    Tack, G. J., Verbeek, W. H., Schreurs, M. W. & Mulder, C. J. The spectrum of celiac disease: epidemiology, clinical aspects and treatment. Nat. Rev. Gastroenterol. Hepatol. 7, 204–213 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Malamut, G., Meresse, B., Cellier, C. & Cerf-Bensussan, N. Refractory celiac disease: from bench to bedside. Semin. Immunopathol. 34, 601–613 (2012).

    Article  Google Scholar 

  17. 17

    Verbeek, W. H. et al. Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in refractory celiac disease. Clin. Immunol. 126, 48–56 (2008).

    CAS  Article  Google Scholar 

  18. 18

    Tack, G. J. et al. Serum parameters in the spectrum of coeliac disease: beyond standard antibody testing—a cohort study. BMC Gastroenterol. 12, 159 (2012).

    CAS  Article  Google Scholar 

  19. 19

    Cellier, C. et al. Abnormal intestinal intraepithelial lymphocytes in refractory sprue. Gastroenterology 114, 471–481 (1998).

    CAS  Article  Google Scholar 

  20. 20

    Schmitz, F. et al. Identification of a potential physiological precursor of aberrant cells in refractory coeliac disease type II. Gut 62, 509–519 (2013).

    CAS  Article  Google Scholar 

  21. 21

    Mention, J. J. et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125, 730–745 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Colpitts, S. L. et al. Cutting edge: the role of IFN-alpha receptor and MyD88 signaling in induction of IL-15 expression in vivo. J. Immunol. 188, 2483–2487 (2012).

    CAS  Article  Google Scholar 

  23. 23

    Rubio-Tapia, A. & Murray, J. A. Classification and management of refractory coeliac disease. Gut 59, 547–557 (2010).

    Article  Google Scholar 

  24. 24

    Al-Toma, A., Verbeek, W. H. & Mulder, C. J. The management of complicated celiac disease. Dig. Dis. 25, 230–236 (2007).

    CAS  Article  Google Scholar 

  25. 25

    Daum, S., Cellier, C. & Mulder, C. J. Refractory coeliac disease. Best Pract. Res. Clin. Gastroenterol. 19, 413–424 (2005).

    Article  Google Scholar 

  26. 26

    Hadithi M et al. Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease. Ann. Intern. Med. 147, 294–302 (2007).

    Article  Google Scholar 

  27. 27

    Vahedi, K. et al. Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease. Am. J. Gastroenterol. 98, 1079–1087 (2003).

    CAS  Article  Google Scholar 

  28. 28

    [No authors listed]. Giardia lamblia and coeliac disease. Lancet 302, 138 (1973).

  29. 29

    Mulder, C. J., Wahab, P. J., Moshaver, B. & Meijer, J. W. Refractory coeliac disease: a window between coeliac disease and enteropathy associated T cell lymphoma. Scand. J. Gastroenterol. Suppl. 2000, 32–37 (2000).

    Google Scholar 

  30. 30

    Abolhassani, H. et al. A review on guidelines for management and treatment of common variable immunodeficiency. Expert Rev. Clin. Immunol. 9, 561–574 (2013).

    CAS  Article  Google Scholar 

  31. 31

    Rubio-Tapia, A., Talley, N. J., Gurudu, S. R., Wu, T. T. & Murray, J. A. Gluten-free diet and steroid treatment are effective therapy for most patients with collagenous sprue. Clin. Gastroenterol. Hepatol. 8, 344–349 (2010).

    Article  Google Scholar 

  32. 32

    Gopal, P. & McKenna, B. J. The collagenous gastroenteritides: similarities and differences. Arch. Pathol. Lab. Med. 134, 1485–1489 (2010).

    PubMed  Google Scholar 

  33. 33

    Gentile, N. M., Murray, J. A. & Pardi, D. S. Autoimmune enteropathy: a review and update of clinical management. Curr. Gastroenterol. Rep. 14, 380–385 (2012).

    Article  Google Scholar 

  34. 34

    Masia, R., Peyton, S., Lauwers, G. Y. & Brown, I. Gastrointestinal biopsy findings of autoimmune enteropathy: a review of 25 cases. Am. J. Surg. Pathol. 38, 1319–1329 (2014).

    Article  Google Scholar 

  35. 35

    Bhat, N., Anupama, N. K., Yelsangikar, A. & Vizhi, K. Olmesartan-related sprue-like enteropathy. Indian J. Gastroenterol. 33, 564–567 (2014).

    Article  Google Scholar 

  36. 36

    Heerasing, N., Hair, C. & Wallace, S. Olmesartan-induced enteropathy. Intern. Med. J. 45, 117–118 (2015).

    CAS  Article  Google Scholar 

  37. 37

    van Beurden, Y. H., Nijeboer, P., Janssen, J., Verbeek, W. H. & Mulder, C. J. Diarrhoea and malabsorption due to olmesartan use [Dutch]. Ned. Tijdschr. Geneeskd. 158, A7370 (2014).

    PubMed  Google Scholar 

  38. 38

    Verbeek, W. H. et al. Incidence of enteropathy—associated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands. Scand. J. Gastroenterol. 43, 1322–1328 (2008).

    Article  Google Scholar 

  39. 39

    Van Weyenberg, S. J., Smits, F., Jacobs, M. A., Van Turenhout, S. T. & Mulder, C. J. Video capsule endoscopy in patients with nonresponsive celiac disease. J. Clin. Gastroenterol. 47, 393–399 (2012).

    Article  Google Scholar 

  40. 40

    Hadithi, M. et al. The value of double-balloon enteroscopy in patients with refractory celiac disease. Am. J. Gastroenterol. 102, 987–996 (2007).

    Article  Google Scholar 

  41. 41

    Mallant, M. et al. Abdominal computed tomography in refractory coeliac disease and enteropathy associated T-cell lymphoma. World J. Gastroenterol. 13, 1696–1700 (2007).

    Article  Google Scholar 

  42. 42

    Van Weyenberg, S. J. et al. Double-balloon endoscopy as the primary method for small-bowel video capsule endoscope retrieval. Gastrointest. Endosc. 71, 535–541 (2010).

    Article  Google Scholar 

  43. 43

    Van Weyenberg, S. J. et al. Comparison of MR enteroclysis with video capsule endoscopy in the investigation of small-intestinal disease. Abdom. Imaging 38, 42–51 (2013).

    Article  Google Scholar 

  44. 44

    Daum, S. et al. Capsule endoscopy in refractory celiac disease. Endoscopy 39, 455–458 (2007).

    CAS  Article  Google Scholar 

  45. 45

    Hadithi, M. et al. 18F-FDG PET versus CT for the detection of enteropathy-associated T-cell lymphoma in refractory celiac disease. J. Nucl. Med. 47, 1622–16227 (2006).

    PubMed  Google Scholar 

  46. 46

    Nijeboer P, van Wanrooij, R. L., Tack, G. J., Mulder, C. J. & Bouma, G. Update on the diagnosis and management of refractory coeliac disease. Gastroenterol. Res. Pract. 2013, 518483 (2013).

    Article  Google Scholar 

  47. 47

    van Wanrooij, R. L. et al. Accurate classification of RCD requires flow cytometry. Gut 59, 1732 (2010).

    CAS  Article  Google Scholar 

  48. 48

    van Wanrooij, R. L. et al. Optimal strategies to identify aberrant intra-epithelial lymphocytes in refractory coeliac disease. J. Clin. Immunol. 34, 828–835 (2014).

    CAS  Article  Google Scholar 

  49. 49

    Brar, P., Lee, S., Lewis, S., Egbuna, I., Bhagat, G. & Green, P. H. Budesonide in the treatment of refractory celiac disease. Am. J. Gastroenterol. 102, 2265–2269 (2007).

    CAS  Article  Google Scholar 

  50. 50

    Jamma, S. et al. Small intestinal release mesalamine for the treatment of refractory celiac disease type I. J. Clin. Gastroenterol. 45, 30–33 (2011).

    CAS  Article  Google Scholar 

  51. 51

    Goerres, M. S. et al. Azathioprine and prednisone combination therapy in refractory coeliac disease. Aliment Pharmacol. Ther. 18, 487–494 (2003).

    CAS  Article  Google Scholar 

  52. 52

    Gillett, H. R. et al. Successful infliximab treatment for steroid-refractory celiac disease: a case report. Gastroenterology 122, 800–805 (2002).

    Article  Google Scholar 

  53. 53

    Costantino, G. et al. Treatment of life-threatening type I refractory coeliac disease with long-term infliximab. Dig. Liver Dis. 40, 74–77 (2008).

    CAS  Article  Google Scholar 

  54. 54

    Tack, G. J., van Asseldonk, D. P., van Wanrooij, R. L., van Bodegraven, A. A. & Mulder, C. J. Tioguanine in the treatment of refractory coeliac disease—a single centre experience. Aliment. Pharmacol. Ther. 36, 274–281 (2012).

    CAS  Article  Google Scholar 

  55. 55

    Malamut, G. et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology 136, 81–90 (2009).

    Article  Google Scholar 

  56. 56

    Al-Toma, A. et al. Cladribine therapy in refractory celiac disease with aberrant T cells. Clin. Gastroenterol. Hepatol. 4, 1322–1327 (2006).

    CAS  Article  Google Scholar 

  57. 57

    Robak, T., Wierzbowska, A. & Robak, E. Recent clinical trials of cladribine in hematological malignancies and autoimmune disorders. Rev. Recent Clin. Trials 1, 15–34 (2006).

    CAS  Article  Google Scholar 

  58. 58

    Al-Toma, A. et al. Cladribine therapy in refractory celiac disease with aberrant T cells. Clin. Gastroenterol. Hepatol. 4, 1322–1327 (2006).

    CAS  Article  Google Scholar 

  59. 59

    Tack, G. J. et al. Evaluation of Cladribine treatment in refractory celiac disease type II. World J. Gastroenterol. 17, 506–513 (2011).

    CAS  Article  Google Scholar 

  60. 60

    Al-Toma, A., Nijeboer, P., Bouma, G., Visser, O. & Mulder, C. J. Hematopoietic stem cell transplantation for non-malignant gastrointestinal diseases. World J. Gastroenterol. 20, 17368–17375 (2014).

    Article  Google Scholar 

  61. 61

    Al-Toma, A. et al. Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T cells. Blood 109, 2243–2249 (2007).

    CAS  Article  Google Scholar 

  62. 62

    Tack, G. J. et al. Auto-SCT in refractory celiac disease type II patients unresponsive to cladribine therapy. Bone Marrow Transplant 46, 840–846 (2011).

    CAS  Article  Google Scholar 

  63. 63

    Wahab, P. J., Crusius, J. B., Meijer, J. W., Uil, J. J. & Mulder, C. J. Cyclosporin in the treatment of adults with refractory coeliac disease—an open pilot study. Aliment. Pharmacol. Ther. 14, 767–774 (2000).

    CAS  Article  Google Scholar 

  64. 64

    Al-Toma, A., Verbeek, W. H., Hadithi M, von Blomberg, B. M. & Mulder, C. J. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut 56, 1373–1378 (2007).

    CAS  Article  Google Scholar 

  65. 65

    Gale, J., Simmonds, P. D., Mead, G. M., Sweetenham, J. W. & Wright, D. H. Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center. J. Clin. Oncol. 18, 795–803 (2000).

    CAS  Article  Google Scholar 

  66. 66

    van de Water, J. M. et al. Enteropathy associated T-cell lymphoma and its precursor lesions. Best Pract. Res. Clin. Gastroenterol. 24, 43–56 (2010).

    Article  Google Scholar 

  67. 67

    Nijeboer, P. et al. Therapy in RCDII: Rationale for Combination Strategies? Dig. Dis. 33, 227–230 (2015).

    Article  Google Scholar 

  68. 68

    Malamut, G. et al. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J. Clin. Invest. 120, 2131–2143 (2010).

    CAS  Article  Google Scholar 

  69. 69

    van der, H. D. et al. Tofacitinib (CP-690550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 65, 559–570 (2013).

    Article  Google Scholar 

  70. 70

    van Vollenhoven, R. F. et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 367, 508–519 (2012).

    CAS  Article  Google Scholar 

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All authors made equal contributions to writing the article. G.B. and C.J.J.M. made substantial contributions to discussion of content and reviewed/edited the manuscript before submission. P.N., R.L.v.W., G.B. and C.J.J.M. researched data for the article.

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Correspondence to Chris J. J. Mulder.

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The authors declare no competing financial interests.

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van Gils, T., Nijeboer, P., van Wanrooij, R. et al. Mechanisms and management of refractory coeliac disease. Nat Rev Gastroenterol Hepatol 12, 572–579 (2015).

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